Kabanat

Uses

In combination with prednisone or prednisolone, for patients with hormone refractory metastatic prostate cancer previously treated with a docetaxel-containing regimen. Due to high incidence of neutropenia, granulocyte-colony stimulating factor (G-CSF) should be administered within 24-72 hr since 1st cycle of Kabanat administration.

Kabanat is also used to associated treatment for these conditions: Refractory, metastatic hormone-refractory Prostate cancer

How Kabanat works

Kabanat is a microtubule inhibitor. Kabanat binds to tubulin and promotes its assembly into microtubules while simultaneously inhibiting disassembly. This leads to the stabilization of microtubules, which results in the interference of mitotic and interphase cellular functions. The cell is then unable to progress further into the cell cycle, being stalled at metaphase, thus triggering apoptosis of the cancer cell.

Dosage

Kabanat dosage

25 mg/m2administered as a 1 hr IV infusion every 3 wk in combination with oral prednisone or prednisolone 10 mg administered daily throughout treatment.

Side Effects

Most commonly in all grades, anemia, leukopenia, neutropenia, thrombocytopenia, diarrhea. Most commonly in ≥3 grade, neutropenia, leukopenia, anemia, febrile neutropenia, diarrhea.

Toxicity

Kabanat may cause serious side effects including neutropenia, hypersensitivity reactions, gastrointestinal symptoms, and renal failure. Anticipated complications of overdose include exacerbation of adverse reactions such as bone marrow suppression and gastrointestinal disorders. Kabanat penetrates the blood-brain barrier. LD50, rat = 500 mg/kg

Precaution

Hypersensitivity reaction; risk of neutropenia; risk of nausea, vomiting, diarrhea, dehydration, peripheral neuropathy; renal failure, cardiac arrhythmias; liver impairment; anemia. Pregnancy & lactation. Elderly.

Interaction

May increase plasma conc with strong CYP3A4 inhibitors. May lead to decreased plasma conc with strong CYP3A4 inducers. Vaccination with a live attenuated vaccine should be avoided.

Food Interaction

• Avoid grapefruit products. Grapefruit inhibits the CYP3A4 metabolism of cabazitaxel, which may increase its serum concentration.
• Avoid St. John's Wort. This herb induces the CYP3A4 metabolism of cabazitaxel and may reduce its serum concentration.

Kabanat Drug Interaction

Moderate: paclitaxel protein-bound, pegfilgrastimUnknown: acetaminophen, aspirin, amphetamine / dextroamphetamine, doxorubicin, ibuprofen, fexofenadine, palonosetron, alprazolam, pseudoephedrine / triprolidine, aspirin, sulfamethoxazole / trimethoprim, apixaban, tamsulosin, cephalexin, leuprolide, acetaminophen, cholecalciferol, abiraterone

Kabanat Disease Interaction

Major: infections, hepatic impairment, myelosuppression, renal failureModerate: GI complications, hemodialysis, pulmonary impairment

Volume of Distribution

The volume of distribution (Vss) was 4,864 L (2,643 L/m2 for a patient with a median BSA of 1.84 m2) at steady state. Compared to other taxanes, penetrates the CNS to a greater extent.

Elimination Route

After an intravenous dose of cabazitaxel 25 mg/m2 every three weeks to a population of 170 patients with solid tumors, the mean Cmax in patients with metastatic prostate cancer was 226 ng/mL (CV 107%) and was reached at the end of the one-hour infusion (Tmax). The mean AUC in patients with metastatic prostate cancer was 991 ng.h/mL (CV 34%). Administration with prednisone or prednisolone do not effect the pharmacokinetic profile of cabazitaxel.

Half Life

Following a one-hour intravenous infusion, plasma concentrations of cabazitaxel can be described by a three-compartment pharmacokinetic model with α-, β-, and γ- half-lives of 4 minutes, 2 hours, and 95 hours, respectively.

Clearance

Kabanat has a plasma clearance of 48.5 L/h (CV 39%; 26.4 L/h/m2 for a patient with a median BSA of 1.84 m2) in patients with metastatic prostate cancer.

Elimination Route

After a one-hour intravenous infusion [14C]-cabazitaxel 25 mg/m2, approximately 80% of the administered dose was eliminated within 2 weeks. Kabanat is mainly excreted in the feces as numerous metabolites (76% of the dose); while renal excretion of cabazitaxel and metabolites account for 3.7% of the dose (2.3% as unchanged drug in urine).

Pregnancy & Breastfeeding use

Pregnancy category D. There is positive evidence of human foetal risk, but the benefits from use in pregnant women may be acceptable despite the risk (e.g., if the drug is needed in a life-threatening situation or for a serious disease for which safer drugs cannot be used or are ineffective).

Contraindication

Neutrophil counts <1,500/mm3; platelets >100,000/mm3, haemoglobin >10 g/dL, creatinine <1.5 x ULN, hepatic impairment (bilirubin ≥1 x ULN, or AST &/or ALT ≥1.5 × ULN); concomitant vaccination with yellow fever vaccine.

Special Warning

Children: The safety and the efficacy of Kabanat in children have not been established.

Elderly: No specific dose adjustment for the use of Kabanat in elderly patients is recommended (see Pharmacology: Pharmacokinetics under Actions, Precautions and Adverse Reactions).

Hepatic Impairment: Kabanat is extensively metabolized by the liver. Patients with mild hepatic impairment [total bilirubin >1 to ≤1.5 x Upper Limit of Normal (ULN) or AST >1.5 x ULN], should have cabazitaxel dose reduced to 20 mg/m2. Administration of cabazitaxel to patients with mild hepatic impairment should be undertaken with caution and close monitoring of safety. Limited efficacy data for cabazitaxel at 15 mg/m2, the maximum tolerated dose in patients with moderate hepatic impairment (total bilirubin >1.5 to ≤3.0 x ULN), are available to recommend this dose in this population. Kabanat should not be given to patients with severe hepatic impairment (total bilirubin >3 x ULN).

Renal Impairment: Kabanat is minimally excreted through the kidney. No dose adjustment is necessary in patients with renal impairment not requiring hemodialysis. Patients presenting end-stage renal disease (CLCR <15 mL/min/1.73 m2), by their condition and the limited amount of available data, therefore these patients should be treated with caution and monitored carefully during treatment.

Concomitant Drug Use: Concomitant drugs that are strong CYP3A inducers or strong CYP3A inhibitors should be avoided (see Pharmacology: Pharmacokinetics under Actions and Interactions). However, if patients require co-administration of a strong CYP3A inhibitor, a 25% cabazitaxel dose reduction should be considered (see Pharmacology: Pharmacokinetics under Actions and Interactions).

Storage Condition

Store between 15-30° C. Do not refrigerate.

Innovators Monograph

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